Many brain functions, including memory formation and acquired neuroprotection, are controlled by transient increases in the intracellular calcium concentration induced by synaptic activity. Calcium can act locally near the site of entry to switch on signaling mechanisms that modulate several biochemical processes that in turn lead to changes in neuronal excitability and/or the efficacy of synaptic transmission. The long-term maintenance of such activity-induced, functional adaptations requires that calcium transients invade the cell nucleus and activate or repress gene expression. Nuclear calcium is one of the most potent signals in neuronal gene expression and represents a key player in the dialogue between synapse and nucleus. It controls cAMP Response Element Binding (CREB)- and CREB-binding protein (CBP)-mediated transcription and is critical for the acquisition of memories and the build-up of neuroprotective activity in synaptically-activated neurons. A picture of how genomic events induced by nuclear calcium signaling regulate persistent neuroprotection is emerging. In contrast, nuclear calcium-regulated processes required for memory formation are unknown. Here, the possibility that nuclear calcium signaling modulates structural features of neurons, in particular the complexity of the dendritic arbor that determines their ability to receive and process inputs, was considered. The calcium/calmodulin dependent protein kinase IV (CaMKIV), a target of calcium in the nucleus, has been implicated in the regulation of dendritic growth and spine remodeling, suggesting that nuclear calcium may represent an important signal in these processes.
The role of neuronal dendrites is to receive and process synaptic inputs. The geometry of the dendritic arbor can undergo neuronal activity-dependent changes, which may impact on the cognitive abilities of the organism. The geometry of dendrites specifies the connectivity of neurons and strongly influences how signals are integrated and transmitted to the cell soma, and, therefore, also which output is produced. Changes in the lengths and branching patterns of dendrites would be expected to alter not only the performance of a neuron but also the computational power of the network the neuron is part of, ultimately causing changes in the organism's behavior.
Shortening and simplification of dendrites have been observed in a variety of disorders that are associated with mental retardation or cognitive deficits, including ischemia, in particular cerebral ischemia, genetic abnormalities, such as Down syndrome or Rett syndrome, neurodegenerative conditions, including Alzheimer's disease and ageing, metabolic dysfunctions and infection with human immunodeficiency virus (HIV).
Therefore, a strong need exists to provide means for modifying the length and/or the complexity of the dendrites of a neuronal cell, which could prove to be useful in the treatment of conditions that would benefit from such modification.